IL-18 is a member of the IL-1 cytokine superfamily. It is an important regulator of innate and adaptive immunity, it synergizes with IL-12 to induce Th1/Tc1 lineage differentiation, induces T and NK cell maturation, stimulates IFNγ, TNF-α and GM-CSF production, regulates macrophage and neutrophil accumulation, function and cellular apoptosis, and contributes to Th2 responses by stimulating IgE production and Th2 differentiation in the presence of IL-4 or IL-2. IL-18 receptor (IL-18R1) consists of a ligand binding (IL-18Rα) and signaling transducing subunits (IL-18Rβ) (reviewed in Nakanishi, K. et al., Ann. Rev. Immunol. 19 (2001) 423-474).
IL-18 appears to modulate inflammation at multiple checkpoints and considered a potential therapeutic target. Previous studies have demonstrated that IFNα and CD8 T-cells plays an important role(s) in the pathogenesis of pulmonary emphysema (Grumelli, S. et al., PLoS Medicine 1 (2004) 75-83; Ma et al., J. Clin. Invest. 115 (2005); 3460-3472; Wang, Z. et al., J. Exp. Med. 192 (2000) 1587-1599; Sutherland and Cherniack, N. Engl. J. Med. 350 (2004) 2689-2697. IL-18 plays an important role in Th1/Tc1 lineage differentiation and cytokine production. Hoshino, T. et al., Am. J. Respir. Crit. Care Med. 176 (2007) 49-62. In a murine model, cigarette smoke (CS) induces and activates IL-18 in mice, IL-18R1α plays a critical role in the pathogenesis and CS-induced inflammation and alveolar destruction (Kang, M. J., et al., J. Immunol. 178 (2007) 1948-1959; Kang, M. J., J. Clin. Invest. 118 (2008) 2771-2784).
Human IL-18R1 (Interleukin-18 receptor 1, IL-18Rα, CD218 antigen-like family member A, CD218a, UniProtKB/Swiss-Prot Q13478; SEQ ID NO:72) is a receptor for interleukin 18 (IL-18) and a Single-pass type I membrane protein. Binding to the agonist leads to the activation of NF-kappa-B. IL-18R1 is expressed in lung, leukocytes, spleen, liver, thymus, prostate, small intestine, colon, placenta, and heart, and is absent from brain, skeletal muscle, pancreas, and kidney. High level of expression are found in Hodgkin disease cell lines. IL-18R1 is mentioned in Parnet, P. et al., J. Biol. Chem. 271 (1996) 3967-3970; Torigoe, K. et al., J. Biol. Chem. 272 (1997) 25737-25742).
IL-18R1 and antibody against IL-18R1 are mentioned U.S. Pat. No. 7,704,945, U.S. Pat. No. 7,615,220, U.S. Pat. No. 7,169,581, U.S. Pat. No. 7,141,393, U.S. Pat. No. 6,600,022, EP1047781, WO2010011697, WO2009015284, WO2009015284, WO2009074634, WO2009015284, WO2007117577, WO2008027236, WO2007117577, WO2007096398, WO2005097998A3, WO2006009114, WO2005097998, WO2005012352, WO2003080104, WO2003057821, WO2003008452A3, WO2003012061, WO2001085201, WO2002008272, WO1999037772.
The object of the invention is to provide antibodies against IL-18R1 which are useful as a therapeutic agent for treatment of inflammatory diseases, like TH1 mediated diseases especially COPD, autoimmune diseases, rheumatoid arthritis, lupus, and psoriasis diseases.